The present invention relates to novel compounds useful as therapeutic, prophylactic or diagnostic agents having binding affinity to integrin receptors, in particular to xcex14 integrins.
The integrins are xcex1/xcex2 heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation (Hynes, Cell 1992, 69, 11-25; Hemler, Annu. Rev. Immunol. 1990, 8, 365-368). Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery (Sharar et al, Springer Semin. Immunopathology 1995, 16, 359-378). In the immune system, integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes (Nakajima et al, J. Exp. Med. 1994, 179, 1145-1154). Differential expression of integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses (Butcher et al, Science 1996, 272, 60-66). The xcex14 integrins, xcex14xcex21 (VLA-4) and xcex14xcex27 (LPAM), are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils (Elices et al, Cell 1990, 60, 577-584). The primary ligands for xcex14 integrins are the endothelial surface proteins mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with lower affinity (Makarem et al, J. Biol. Chem. 1994, 269, 4005-4011). The binding of the xcex14xcex21 or xcex14xcex27 to MAdCAM and/or VCAM expressed on high endothelial venules (HEVs) at sites of inflammation results in firm adhesion of the leukocyte to the endothelium followed by extravasation into the inflamed tissue (Chuluyan et al, Springer Semin. Immunopathology 1995, 16, 391-404). Monoclonal antibodies directed against xcex14xcex21, (xcex14xcex27, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Simmons et al, Blood 1992, 80, 388-395), rheumatoid arthritis (RA) (Juliano et al, Current Opinion Cell Biology 1993, 5, 812-818), and inflammatory bowel diseases (IBD) (Laberge et al, Am. J. Respir. Crit Care Med. 1995, 151, 822-829 and Barbadillo et al, Springer Semin. Immunopathology 1995, 16). While antibodies have shown efficacy they must be administered parenterally and are inherently cumbersome to produce. Accordingly, it would be desirable to provide small molecule compounds which inhibit the interaction between xcex14 integrins and ligands MAdCAM and/or VCAM which would be useful for treatment of chronic inflammatory diseases such as arthritis, asthma, multiple sclerosis, Chrohn""s disease, ulcerative colitis, and hepatitis C.
According to an aspect of the present invention there is provided compounds of formula (I) 
wherein
A is a 5 or 6 member, saturated or unsaturated carbocycle or heterocycle optionally substituted by oxo and R4;
Q is alkyl, alkenyl or alkynyl optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR6, S, SO, or SO2;
X is xe2x80x94CR5xe2x80x94 or xe2x80x94Nxe2x80x94;
Y is H, xe2x80x94CHR3xe2x80x94, xe2x80x94CR3xe2x95x90, or a bond;
Z is H, xe2x80x94CHR3xe2x80x94, xe2x95x90CR3xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x95x90Nxe2x80x94, O, S, SO, SO2 or a bond, provided that when one of Y and Z is H then the other is also H;
W is xe2x80x94C(O)NR6xe2x80x94, xe2x80x94NR6C(O)xe2x80x94, xe2x80x94C(S)NR6xe2x80x94, xe2x80x94NR6C(S)xe2x80x94, NR6, O, S, SO2, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x80x94, xe2x80x94NR6SO2xe2x80x94, xe2x80x94SO2NR6xe2x80x94, xe2x80x94OC(O)NR6xe2x80x94, xe2x80x94NR6C(O)Oxe2x80x94, xe2x80x94OC(S)NR6xe2x80x94, xe2x80x94NR6C(S) Oxe2x80x94, xe2x80x94Sxe2x80x94C(S)NR6xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR6C(O)NR6xe2x80x94 or xe2x80x94NR6C(S)NR6xe2x80x94;
R1 is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle; or R1 is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro;
R2 is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with halogen, hydroxyl, oxo alkoxy, amino, nitro, carboxyl, carboxamido, acyl, acyloxy, amidinyl, guanidinyl, thiol, alkylthio, or one or more carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl; or R2 is a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino, nitro, carboxyl, acyl, acyloxy, alkyl, alkenyl, alkynyl or a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl;
R3 and R4 are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR6, O, S, SO or SO2;
R5 is H or alkyl, alkenyl or alkynyl optionally having a carbon atom replaced with O, N or NR6, and optionally substituted with COOR1; or R5 together with the carbon atom from which it depends forms a double bond to an adjacent carbon or nitrogen atom of Q; or R5 together with a non-adjacent carbon or nitrogen atom of Q form a carbocycle or heterocycle;
R6 is hydrogen, alkyl, alkenyl or alkynyl;
m and n are independently 1, 2 or 3;
and salts, solvates and hydrates thereof.
In another aspect of the invention, there is provided pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, excipient or adjuvant.
In another aspect of the invention, there is provided a method of inhibiting binding of an xcex14 integrin to a protein ligand comprising contacting said xcex14 integrin with a compound of the invention.
In another aspect of the invention, there is provided a method of treating a disease or condition mediated by xcex14 integrin receptors or ligands of xcex14 integrin receptors in a mammal, the method comprising administering to said mammal an effective amount of a compound of the invention.
Compounds are provided having binding affinity for xcex14 integrins, having the general formula (I) 
wherein A, Q, W, X, Y, Z, R1 to R4, m and n are as defined herein.
Ring A is a 5 or 6 member, saturated or unsaturated carbocycle or heterocycle optionally substituted by oxo (xe2x95x90O) and R4. By xe2x80x9ccarbocyclexe2x80x9d is meant herein to be a mono- bi- or tricyclic ring system containing a 4-16 carbon atom scaffold that is saturated, partially unsaturated or fully unsaturated including aromatic. In the context of ring A, suitable carbocycles include cycloalkyl, cycloalkenyl and aryl. In a preferred embodiment, ring A is a carbocycle selected from the group consisting of cyclopentyl, cyclohexyl and benzene. In a most preferred embodiment ring A is benzene. In another embodiment, ring A is a heterocycle. By xe2x80x9cheterocyclexe2x80x9d is meant herein to be a mono-, bi- or tricyclic ring system comprising a combination of 4-16 carbon and hetero atoms (i.e. N, O, and S, as well as SO and SO2) that is saturated, partially unsaturated or fully unsaturated including aromatic. In the context of ring A, preferred heterocycles are 5 and 6 member monocycles. Particularly preferred ring A heterocycles include pyridine, pyran, pyrimidine, pyrazine, pyridazine, pyrole, furan, thiophene, imidazole, pyrazole, thiazole and triazole. It is appreciated that ring A encompasses heterocycles in which the heteroatoms may be shared with the central ring, if present, and/or may be adjacent to X.
Q is a divalent alkyl, alkenyl or alkynyl linking group optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR6, S, SO, or SO2. In a preferred embodiment, Q is alkyl having 1 to 3 carbon atoms or methylene groups in length, and more preferably length of 2 methylene groups. In another preferred embodiment, the methylene group adjacent to the group X is replaced with a nitrogen atom or NR6 and more preferably with an oxygen atom. In a particularly preferred embodiment, Q is xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein the oxygen atom is adjacent to the X group.
X is a bridging group xe2x80x94CR5xe2x80x94 or xe2x80x94Nxe2x80x94 from which the group Q depends. In a preferred embodiment, X is xe2x80x94CR5xe2x80x94 wherein R5 is H. In another embodiment R5 is alkyl, alkenyl or alkynyl optionally having a carbon atom replaced with O, N or NR6, and is optionally substituted with COOR1. By xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d is meant herein to be straight or branched aliphatic groups having 1-10 carbon atoms, preferably 1-6 and more preferably 1-4. Preferred alkyl groups are methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Preferably, R5 is an alkyl group having 1 to 3 carbon atoms or methylene groups in length and is substituted with COOR1. More preferably, R5 is xe2x80x94(CH2)2xe2x80x94COOR1. In another embodiment, R5 together with the carbon atom from which it depends forms a double bond to an adjacent carbon or nitrogen atom of Q. In yet another embodiment R5 together with a non-adjacent carbon or nitrogen atom from the group Q form a carbocycle or heterocycle. In this context, a preferred embodiment is when R5 and the carbon atom in Q which is beta to the group X form a 1,3-dioxolane ring. In a particularly preferred embodiment, the dioxolane ring is spiro at X and the two oxygen atoms are alpha to the X group.
Y is H, xe2x80x94CHR3xe2x80x94, xe2x80x94CR3xe2x95x90, or a bond and Z is H, xe2x80x94CHR3xe2x80x94, xe2x95x90CR3xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x95x90Nxe2x80x94, O, S, SO, SO2 or a bond, provided that when one of Y and Z is H then the other is also H. In a preferred embodiment, one of Y and Z is a bond while the other is xe2x80x94CHR3xe2x80x94 thereby forming a six member ring fused to ring A and the benzene ring of formula (I) resulting in a tricyclic ring system. In another preferred embodiment Y and Z are both xe2x80x94CHR3xe2x80x94 thereby forming a seven member ring. In a more preferred embodiment, Y and Z are both H wherein ring A and the benzene ring of formula (I) are linked via group X rather than forming a fused tricyclic ring system. In a more preferred embodiment, Y and Z are both a bond thereby forming a five member ring fused to ring A and the benzene ring, and in a most preferred embodiment the five member ring together with ring A and the benzene ring of formula (I) form a fluorenyl ring.
W is xe2x80x94C(O) NR6xe2x80x94, xe2x80x94NR6C(O)xe2x80x94, xe2x80x94C(S)NR6xe2x80x94, xe2x80x94NR6C(S)xe2x80x94, NR6, O, S, SO2, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x80x94, xe2x80x94NR6SO2xe2x80x94, xe2x80x94SO2NR6xe2x80x94, xe2x80x94OC(O)NR6xe2x80x94, xe2x80x94NR6C(O)Oxe2x80x94, xe2x80x94OC(S)NR6xe2x80x94, xe2x80x94NR6C(S)Oxe2x80x94, xe2x80x94Sxe2x80x94C(S)NR6xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR6C(O)NR6xe2x80x94 or xe2x80x94NR6C(S)NR6xe2x80x94. In a particular embodiment W is the amido group xe2x80x94C(O)NR6xe2x80x94 wherein the nitrogen atom is adjacent to the benzene ring of formula (I), or alternatively xe2x80x94NR6C(O)xe2x80x94 wherein the carbonyl is adjacent to the benzene ring. In another particularly embodiment W is the sulfonamido group xe2x80x94NR6SO2xe2x80x94 wherein the sulfur atom is adjacent to the benzene ring, or alternatively xe2x80x94SO2NR6xe2x80x94 wherein the nitrogen atom is adjacent to the benzene ring. In the context where W is amido or sulfonamido, R6 is preferably H or C1-4 alkyl and more preferably H or methyl. In another particular embodiment, W is O. In a particularly preferred embodiment W is NR6 wherein R6 is H or C1-4 alkyl and particularly H or methyl.
R1 is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle. By xe2x80x9caminoxe2x80x9d is meant herein to be a primary, secondary or tertiary amine substituted with alkyl, alkenyl, alkynyl, aryl, or aralkyl each optionally substituted as provided herein. By xe2x80x9ccarboxylxe2x80x9d is meant herein to be xe2x80x94COOH as well as carboxy ester groups thereof and in particular alkyl esters thereof. Alternatively R1 is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro. In a preferred embodiment R1 is H or a group which is liberated in vivo to yield a free carboxy group xe2x80x94C(O)Oxe2x88x92.
R2 is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with halogen, hydroxyl, oxo (xe2x95x90O), alkoxy, amino, nitro, carboxyl, carboxamido, acyl, acyloxy, amidinyl (xe2x80x94C(NH)NHxe2x80x94 or xe2x80x94NHC(NH)xe2x80x94), guanidinyl (xe2x80x94NHC(NH)NHxe2x80x94), thiol, alkylthio, or one or more carbocycle or heterocycle optionally substituted with halogen (F, Cl, Br or I), hydroxyl, oxo, alkoxy, amino or carboxyl. By xe2x80x9calkoxyxe2x80x9d is meant herein to include xe2x80x94O-alkyl, xe2x80x94O-alkenyl and xe2x80x94O-alkynyl wherein alkyl, alkenyl and alkynyl are as previously defined. By xe2x80x9cacylxe2x80x9d is meant herein to be a substituted carbonyl (xe2x80x94C(O)xe2x80x94). Suitable acyl groups include alkanoyl, aroyl and aralkanoyl. Suitable acyloxy groups include alkanoyloxy, aroyloxy and aralkanoyloxy. In a particularly preferred embodiment R2 is a naturally occurring or non-naturally occurring D or L-amino acid residue in which the alpha nitrogen or alpha amino group is optionally acylated. In particularly preferred embodiments, W is NR6 and R2 is N-acetyl-tyrosine, D-tyrosine, phenylalanine, benzoyl, isonipecotoyl, 4-methoxyphenylacetyl, 1-fluorenyl-carbonyl, 1-naphthoyl, 2-naphthoyl, 3-hydroxy-phenylalanine, 3-iodo-tyrosine, 3-fluoro-tyrosine, 3-chloro-tyrosone, 4-(4-hydroxyphenyl)-benzoyl, 2,3,5,6-tetrafluoro-tyrosine, 6-hydroxynaphthoyl, 2-phenyl-3-(4-hydroxyphenyl)propanoyl and N-acetyl-3-(4-hydroxyphenyl)proline. In a more preferred embodiment R2 is a tyrosine amino acid reside and more preferably a tyrosine residue wherein the alpha nitrogen is acylated with acetyl (i.e. N-acetyl tyrosine).
In another embodiment R2 is a carbocycle or heterocycle optionally substituted with one or more halogen, hydroxyl, oxo, alkoxy, amino, nitro, carboxyl, acyl, acyloxy, alkyl, alkenyl, alkynyl or a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl. In a particular embodiment R2 is a heterocycle substituted with a phenyl group which in turn is optionally substituted with one or more halogen, hydroxyl, alkoxy or carboxyl. In a particularly preferred embodiment, the heterocycle is a pyrrolidine ring such that when W is an amido group xe2x80x94C(O)NR6xe2x80x94 or xe2x80x94NR6C(O)xe2x80x94R2 and W together form a proline amino acid residue. The proline residue is preferably substituted at its beta carbon (i.e. 3-position of the pyrrolidine ring) with a phenyl group which is optionally para-substituted (i.e. at its 4-position) with hydroxyl thereby forming a constrained tyrosine residue. The phenyl group is optionally substituted at one or more of the 2, 3, 5 and 6 positions with a halogen, in particular iodo (I), chloro (Cl) or fluoro (I). Further, the nitrogen atom of the proline residue is optionally acylated, in particular with an alkanoyl group such as acetyl.
R3 and R4 are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR6, O, S, SO or SO2. In a particular embodiment R3 and R4 are H. Alternatively, one or both of R3 and R4 are a carboxy group xe2x80x94COOR1 linked to the ring from which it depends via a linking group such as an alkyl chain of 1-6 methylene groups in length and preferably 1-3 methylene groups. The linking group may depend from the ring by a functional group such as O (alkoxy), NR6 (amino), an amido group or a sulfonamido group. In a preferred embodiment, both xe2x80x98mxe2x80x99 and xe2x80x98nxe2x80x99 are the integer 1.
R6 is hydrogen, alkyl, alkenyl or alkynyl. In a preferred embodiment R6 is C1-4 alkyl and more preferably methyl. In another more preferred embodiment R6 is H.
In accordance with a preferred embodiment, compounds of the invention have the general formula (II): 
wherein
Q is alkyl, alkenyl or alkynyl optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR6, S, SO, or SO2;
R1 is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle; or R1 is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro;
R3 and R4 are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR6, O, S, SO or SO2;
R6 is hydrogen, alkyl, alkenyl or alkynyl;
R7 is hydrogen, hydroxyl, halogen, alkyl, alkoxy or halogen substituted alkyl;
R8 is H, alkyl, alkenyl or alkynyl;
R9 is H or NR11R11xe2x80x2 wherein R11 and R11xe2x80x2 are independently H, acyl or and amino acid residue; or one of R11 and R11xe2x80x2 together with R8 form a heterocycle;
R10 is O or S;
m and n are independently 1, 2 or 3;
p is an integer from 1 to 5;
and salts, solvates and hydrates thereof.
In a preferred embodiment R7 is hydroxyl at the para-position (i.e. 4-position) of the phenyl group. Further R7 substituents as provided when xe2x80x98pxe2x80x99 is the integer 2, 3, 4 or 5, include 3-iodo, 3-fluoro, 3-chloro and 2,3,5,6-tetrafluoro.
In particular embodiments, R6 and R8 are H and R10 is oxygen. Alternatively, R6 is methyl.
In a preferred embodiment, R9 is NR11R11xe2x80x2 wherein R11 is H and R11xe2x80x2 is H or acyl, in particular alkanoyl i.e. acetyl. In another preferred embodiment, R9 is NR11R11xe2x80x2 wherein one of R11 and R11xe2x80x2 together with R8 form a 5-member heterocycle while the other of R11 and R11xe2x80x2 is H or C1-4 alkanoyl. Preferably R11 and R8 together form a pyrrolidine ring and R11xe2x80x2 is H or alkanoyl i.e. acetyl.
Particular compounds of the invention include: 
and salts, solvates and hydrates thereof.
It will be appreciated that compounds of the invention may incorporate chiral centers and therefore exist as geometric and stereoisomers. All such isomers are contemplated and are within the scope of the invention whether in pure isomeric form or in mixtures of such isomers as well as racemates. Stereoisomeric compounds may be separated by established techniques in the art such as chromatography, i.e. chiral HPLC, or crystallization methods.
xe2x80x9cPharmaceutically acceptablexe2x80x9d salts include both acid and base addition salts. Pharmaceutically acceptable acid addition salt refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
Compounds of the invention may be prepared according to established organic synthesis techniques from starting materials and reagents that are commercially available. In general, the compounds may be prepared starting from a commercially available central ring system. Depending on the particular compound to be prepared, the central ring system is manipulated to append first the carboxylate moiety xe2x80x94Qxe2x80x94C(O)Oxe2x80x94R1 to X and then the R2xe2x80x94Wxe2x80x94 moiety to the benzene ring, or alternatively first appending the R2xe2x80x94Wxe2x80x94 moiety and then the xe2x80x94Qxe2x80x94C(O)Oxe2x80x94R1 moiety.
In a particular embodiment, compounds of formula (Ia), wherein X is C and Q incorporates an oxygen adjacent to X (i.e. an ether), are prepared according to the general scheme 1. 
Referring to scheme 1, starting compound (i), wherein A, Y, Z, W, R2xe2x80x94R4, m and n are as previously defined, is reduced with a suitable reducing agent, such as sodium borohydride (NaBH4) or equivalent hydride, to give alcohol (ii). Depending on the particular substituents, starting compound (i) may be commercially available or is otherwise prepared according to established organic synthetic techniques from compounds that are commercially available. The final ether compound (Ia) of the invention is achieved by treating alcohol (ii) with an base such as NaH followed by reacting with elecrophilic intermediate (iii), wherein L is a suitable leaving group such as a halogen i.e. Br, and Qxe2x80x2 is the same as Q, i.e. a carboxyl substituted alkyl, alkenyl or alkynyl chain, minus the first carbon atom that would be adjacent to the ring system. It will be appreciated that depending on the particular substituents present in the compound, suitable protection and deprotection procedures will be required as is standard in the art. Numerous protecting groups are described in Greene and Wuts, Protective Groups in Organic Chemistry, 2d edition, John Wiley and Sons, 1991, as well as detailed protection and deprotection procedures. For example, suitable amino protecting groups include t-butyloxycarbonyl (Boc), fluorenyl-methyloxycarbonyl (Fmoc), 2-trimethylsilyl-ethyoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), allyloxycarbonyl (Alloc), and benzyloxycarbonyl (Cbz). Carboxyl groups can be protected as fluorenylmethyl groups and hydroxyl groups may be protected with trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl groups.
Preparation of compounds of the invention wherein X is carbon and Q is an alkyl chain, may be accomplished according to scheme 2. 
Referring to scheme 2, starting compound (i) is reacted with a non-nucleophilic base such as NaH, LDA or TBAF, to give carbanion (ii) which is subsequently reacted with intermediate (iii) to yield compound of formula (Ib) of the invention. In a particular embodiment wherein Q is and optionally substituted C2 alkyl linker to xe2x80x94COOR1, intermediate carbanion (ii) is reacted with an xcex1, xcex2 unsaturated carboxylate (iv) wherein each R is independently hydrogen, halogen, alkyl, carboxyl or aryl, to give compound (Ib) of the invention. Preferably R is halogen or C1-4 alkyl i.e. methyl.
In another embodiment, compounds of formula (I), wherein X is N, are prepared according to scheme 3. 
Referring to scheme 3, starting compound (i) is reacted with intermediate (ii) wherein L is a suitable leaving group, i.e. Br, in the presence of a non-nucleophilic base such as Cs2CO3 or KCO3 to yield the final compound (Ic) of the invention. Alternatively, starting compound (i) can be reacted with an xcex1, xcex2 unsaturated carboxylate (iii) as in scheme 2 to give compound (Ic) of the invention.
In another embodiment, compounds of formula (I) wherein W is xe2x80x94C(O)NHxe2x80x94, xe2x80x94SO2NHxe2x80x94 or xe2x80x94NHxe2x80x94 are prepared according to scheme 4. 
Referring to scheme 4, from the starting amine compound (i) may be prepared amide (Id), sulfonamide (Ie), amine (If), carbamate (Ig) and urea (Ih) by reacting (i) respectively with intermediates (ii) an activated ester of R2xe2x80x94CO2H, (iii) R2xe2x80x94SO2-L wherein L is a leaving group such as a halogen, (iv) R2-L in the presence of a non-nucleophilic base or R2xe2x80x94C(O)H in the presence of NaCNBH3, (v) R2xe2x80x94OC(O)-L, and (vi) isocyanate R2xe2x80x94Nxe2x95x90Cxe2x95x90O. It will be appreciated that thioamides may be prepared in a similar manner as the amides by using R2xe2x80x94C(S)H or R2xe2x80x94C(S)Oxe2x80x94; and thiocarbamates may be prepared using R2xe2x80x94Sxe2x80x94C(O)-L or R2xe2x80x94OC(S)-L; and thioureas may be prepared using isothiocyanate R2xe2x80x94Nxe2x95x90Cxe2x95x90S. In a particular
In another embodiment, compounds of formula (I) wherein W is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 may be prepared according to scheme 5a and 5b. 
Referring to schemes 5a and 5b, the starting hydroxyl or thiol compound is reacted with a non-nucleophilic base such as NaH to remove a proton. The anion is then reacted with R2-L wherein L is a suitable leaving group to yield the resulting ether (Ii) and thioether (Ij) compound of the invention.
In another embodiment compounds of formula (I), wherein W is carbonyl xe2x80x94C(O)xe2x80x94, may be prepared according to scheme 6. 
Referring to scheme 6, starting compound (i) is reacted with aldehyde intermediate (ii) in the presence of NaCNBH3 to give compound (Ik) of the invention.
In another embodiment, compounds of formula (I), wherein W is xe2x80x94NR6SO2xe2x80x94, are prepared according to scheme 7. 
Referring to scheme 7, starting compound (i) is reacted with sulfuric acid and then POCl3 to give the sulfonyl chloride compound (iii) which is reacted with R2xe2x80x94NH2 to give compound (Il) of the invention.
In another embodiment, compounds of formula (I), wherein W is C, may be prepared according to scheme 8. 
Referring to scheme 8, starting compound (i) is reacted with Pdxc2x0 catalyst followed by R2xe2x80x94B(OH)2 or R2xe2x80x94Cxe2x89xa1CH to give final compound (Im) or (In) respectively.
In another embodiment, compounds of formula (I), wherein W is carbamate xe2x80x94NR6C(O)Oxe2x80x94 or thiocarbamate xe2x80x94NR6C(S)Oxe2x80x94, may be prepared according to scheme 9. 
Referring to scheme 9, starting alcohol compound is reacted with intermediate R2xe2x80x94NC(O)-L or R2xe2x80x94NC(S)-L, wherein L is a suitable leaving group such as Br, to give final compound of the invention (Io) or (Ip) respectively. In a particular embodiment, a morpholino carbamate compound of the invention by reacting the starting alcohol with morpholine-C(O)xe2x80x94Cl.
In another embodiment, compounds of formula (I), wherein W is thiocarbamate xe2x80x94NR6C(O)Sxe2x80x94 or thiocarbamate xe2x80x94NR6C(S)Sxe2x80x94, may be prepared according to scheme 10. 
Referring to scheme 10, starting thiol compound (i) is reacted with intermediate R2xe2x80x94NC(O)-L or R2xe2x80x94NC(S)-L, wherein L is a suitable leaving group such as Br, to give final compound of the invention (Iq) or (Ir) respectively.
In an aspect of the invention, there is provided a method of inhibiting binding of an xcex14 integrin to a ligand, the method comprising contacting said xcex14 integrin with a compound of formula (I). The method may be carried out as a solution based or cell based assay wherein the compound of the invention is introduced to the integrin in the presence of a putative or known ligand of the integrin. The compound may be labeled, for example isotopically radiolabeled, to facilitate detection of ligand binding or lack thereof to the integrin. Thus compounds of the invention are useful for diagnostic assays.
Compounds of the invention are useful to prevent the interaction of an epithelial cell bearing VCAM-1 and/or MAdCAM on the cell surface with a leukocyte cell bearing xcex14xcex21 and/or xcex14xcex27 on the surface by contacting the epithelial cell or the leukocyte with an inhibitory amount of the compound of the invention. The compounds are useful in assays to determine the inhibitory effect of a compound which antagonizes the binding of xcex14xcex21 and/or xcex14xcex27 integrin to VCAM-1 ligand and/or MAdCAM ligand. The inhibitory compound may be a small molecule, a protein or peptide or an antibody. In an in vitro assay, the ligand or the integrin may be directly or indirectly bound to a surface, such as microtiter plate, using known methods described for example in WO 9820110, WO 9413312, WO 9624673, Wo 9806248, WO 9936393, and WO 9910312. The other member of the binding pair, e.g. the integrin or the ligand, respectively, (or a cell expressing the same on its surface) is then added to the surface bound member and the inhibitory effect of a test molecule is determined. The inhibitory activity of the compounds of the invention can also be determined with this type of assay.
The binding of the integrins to their respective ligands is known to be involved in inflammatory conditions associated with leukocyte infiltration of tissues lined with epithelial cells expressing VCAM-1 or MAdCAM. Such tissues include the gastrointestinal tract, skin, urinary tract, respiratory airways and joint synovial tissues. The compounds of the invention are useful in treating diseases in which such binding is implicated as a cause of the disease or symptoms of the disease. Undesired disease symptoms may arise from cell adhesion and/or cell activation which releases proinflammatory mediators, typically when there is an increase or upregulation in the expression of VCAM-1 and/or MAdCAM on the surface of endothelial cells. Various disease states which can be treated and for which the inflammatory symptoms can be reduced upon administration of the compounds of the invention include rheumatoid arthritis, asthma, psoriasis, multiple sclerosis, inflammatory bowel disease including ulcerative colitis, pouchitis and Crohn""s disease, Celiac disease, nontropical Sprue, graft-versus-host disease, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, pericholangitis, chronic sinusitis, chronic bronchitis, pneumonitis, collagen disease, eczema, and systemic lupus erythematosis. Compounds of the invention are useful in treating these diseases and conditions by inhibiting the integrin/ligand binding. Compounds of the invention are therapeutically and/or prophylactically useful for treating diseases or conditions mediated by xcex14 integrin receptors i.e. xcex14xcex21 and xcex14xcex27, and/or their ligands, in particular VCAM-1 and MADCAM-1. Accordingly in an aspect of the invention, there is provided a method of treating a disease or condition mediated by the xcex14 integrin receptors or ligands of xcex14 integrin receptor ligands in a mammal, for example a human, comprising administering to said mammal an effective amount of a compound of the invention. By xe2x80x9ceffective amountxe2x80x9d is meant an amount of compound which upon administration is capable of reducing the amount of ligand able to bind to xcex14 integrins in vivo; or an amount of compound which upon administration is capable of alleviating or reducing the severity of symptoms associated with the disease or condition mediated by xcex14 integrins or ligands thereof.
The actual amount of compound administered and the route of administration will depend upon the particular disease or condition as well as other factors such as the size, age, sex and ethnic origin of the individual being treated and is determined by routine analysis. In methods of the invention, the compound may be administered orally (including buccal, sublingual, inhalation), nasally, rectally, vaginally, intravenously, intradermally, subcutaneously and topically. Compounds will be formulated into compositions suitable for administration for example with suitable carriers, diluents, thickeners, adjuvants etc. as are routine in the formulation art. Accordingly, another aspect of the invention provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, excipient or adjuvant. Compositions of the invention may also include additional active ingredients. Dosage forms include solutions, powders, tablets, capsules, gel capsules, suppositories, topical ointments and creams and aerosols for inhalation. Formulations for non-parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic carrier substances suitable for non-parenteral administration which do not deleteriously react with compounds of the invention can be used. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings flavorings and/or aromatic substances and the like which do not deleteriously react with compounds of the invention. Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.
In a preferred embodiment, compounds of the invention are administered via oral delivery. Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, troches, tablets or SECs (soft elastic capsules or caplets). Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, carrier substances or binders may be desirably added to such formulations. Such formulations may be used to effect delivering the compounds to the alimentary canal for exposure to the mucosa thereof. Accordingly, the formulation can consist of material effective in protecting the compound from pH extremes of the stomach, or in releasing the compound over time, to optimize the delivery thereof to a particular mucosal site. Enteric coatings for acid-resistant tablets, capsules and caplets are known in the art and typically include acetate phthalate, propylene glycol and sorbitan monoleate.
Various methods for producing formulations for alimentary delivery are well known in the art. See, generally Remington""s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990. The formulations of the invention can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5% to about 99% by weight of the total mixture, that is to say in amounts which are sufficient to achieve the desired dosage range. The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifying agents and/or dispersing agents, and, for example, in the case where water is used as the diluent, organic solvents can be used as auxiliary solvents if appropriate.
Compositions may also be formulated with binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. The preparations may also contain flavoring, coloring and/or sweetening agents as appropriate.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing predetermined amounts of the active ingredients; as powders or granules; as solutions or suspensions in an aqueous liquid or a non-aqueous liquid; or as oil-in-water emulsions or water-in-oil liquid emulsions. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein.